Autocatalysis in Eschenmoser Coupling Reactions.

The Eschenmoser coupling reaction (ECR) of thioamides with electrophiles is believed to proceed via thiirane intermediates. However, little is known about converting the intermediates into ECR products. Previous mechanistic studies involved external thiophiles to remove the sulfur atom from the intermediates. In this work, an ECR proceeding without any thiophilic agent or base is studied by electrospray ionization-mass spectrometry. ESI-MS enables the detection of the so-far elusive polysulfide species Sn , with n ranging from 2 to 16 sulfur atoms, proposed to be the key species leading to product formation. Integrating observations from ion mobility spectrometry, ion spectroscopy, and reaction monitoring via flow chemistry coupled with mass spectrometry provides a comprehensive understanding of the reaction mechanism and uncovers the autocatalytic nature of the ECR reaction.

Switchable cyclopalladation of substrates containing two directing groups: on the way to non-symmetrical [2.2]-dipalladaparacyclophanes.

Simple switching of the site-selectivity of C-H activation reactions of substrates containing multiple directing groups is particularly important for the so-called late stage functionalization synthetic approach. In this work, we verified the possibility of achieving this by adding acids of different strengths. Using a substrate containing two differently strong (and basic) directing groups, the influence of the addition of acids on the regioselectivity of the C-H activation step of the reaction with palladium acetate was thoroughly studied. The addition of no or weak acids results in cyclopalladation being controlled by a stronger directing group. However, the addition of a strong acid causes protonation of this group and the reaction is then controlled by a weaker directing group. Finally, this approach enables double C-H activation leading to a unique class of compounds: "non-symmetrical" [2.2]-dipalladaparacyclophanes.

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

Carboxamide substituted tetramethylcyclopentadiene - synthesis, characterisation and its iridium(III) complex catalysed reduction of imines.

The novel dimeric iodo-iridium(III) complex, [Ir(Cp*CONMe2)I2]2, (Cp*CONMe2 = η5-N,N-2,3,4,5-hexamethylcyclopenta-2,4-diene carboxamide) bearing an amide moiety within the tetramethylcyclopentadiene ring, has been synthesised and characterised. The ligand Cp*CONMe2 is synthesised as two regioisomers, however the 2-substituted isomer exists as two distinguishable conformers due to restricted rotation about the amide carbonyl carbon and the ring carbon. The relative acidities of Cp*CONMe2 and Cp* are compared by their relative rates of H/D exchange. The iridium complex of N,N-2,3,4,5-hexamethylcyclopenta-2-4-diene carboxamide [IrCp*CONMe2] and (R,R)-1,2-diphenyl-N'-tosylethane-1,2-diamine ((R,R)-TsDPEN) has been evaluated in the transfer hydrogenation of imines under acidic conditions - a 5 : 2 molar ratio of formic acid : triethylamine as the hydride source for the transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline (DHIQ) and its 6,7-dimethoxy derivative in acetonitrile. A decreasing enantiomeric excess with reaction progress is attributed to different kinetic orders for formation of the two product amine enantiomers. The pseudo zero-order formation of the R-amine may be due to a pre-steady-state formation of the less stable form of the diastereomeric catalyst. By contrast, both enantiomeric amines from 1-fluorinated methyl DHIQs as substrates for reduction are formed by pseudo first-order processes.

Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction.

A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitors including Nintedanib and Hesperadin in yields exceeding 76%. Starting compounds for the synthesis are also easily available in good yields. 3-Bromooxindoles were prepared either from corresponding isatins using a three-step synthesis in an average overall yield of 65% or by direct bromination of oxindoles (yield of 65-86%). Starting N-(4-piperidin-1-ylmethyl-phenyl)-thiobenzamide was prepared by thionation of the corresponding benzanilide in an 86% yield and N-methyl-N-(4-thiobenzoylaminophenyl)-2-(4-methylpiperazin-1-yl)acetamide was prepared by thioacylation of the corresponding aniline with methyl dithiobenzoate in an 86% yield.

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction.

A highly modular method for the synthesis of (Z)-3-[amino(phenyl/methyl)methylidene]-1,3-dihydro-2H-indol-2-ones starting from easily available 3-bromooxindoles or (2-oxoindolin-3-yl)triflate and thioacetamides or thiobenzamides is described. A series of 49 compounds, several of which have previously been shown to possess significant tyrosin kinase inhibiting activity, was prepared in yields varying mostly from 70 to 97% and always surpassing those obtained by other published methods. The method includes an Eschenmoser coupling reaction, which is very feasible (even without using a thiophile except tertiary amides) and scalable. The (Z)-configuration of all products was confirmed by NMR techniques.

C-H Functionalizations by Palladium Carboxylates: The Acid Effect.

Finding optimal reaction conditions is usually complex, requires many experiments, and is therefore demanding in terms of human, financial, and environmental resources. This work provides a simple workflow for easier design of popular palladium-catalyzed C-H functionalization reactions, where the active palladium catalysts contain carboxylate ligands. The key factor for optimizing reaction conditions is to find a balance between two opposing effects of the carboxylic acid in the reaction mixture: generation of more reactive palladium catalyst versus deactivation of a substrate by its protonation.

[3 + 2]-Cycloaddition reaction of sydnones with alkynes.

This review covers all known examples of [3 + 2]-cycloaddition between sydnones and both terminal as well as internal alkynes/cycloalkynes taken from literature since its discovery by Huisgen in 1962 up to the current date. Except enumeration of synthetic applications it also covers mechanistic studies, catalysis, effects of substituents and reaction conditions influencing reaction rate and regioselectivity.

Bi and trinuclear complexes in palladium carboxylate-assisted C-H activation reactions.

The role of polynuclear species in C-H activations assisted by palladium carboxylates has not been clear so far. The summary of the key findings covering this issue shows its important role under certain conditions. However, much more effort is necessary for a deeper understanding of the whole issue.

The role of trinuclear species in a palladium acetate/trifluoroacetic acid catalytic system.

Reactions catalyzed by palladium(ii) acetate and trifluoroacetic acid (TFA) have a clear preactivation phase. However, the structure of real catalytic species remains unclear. We show that the key species are cyclic trinuclear complexes of composition [Pd3(OAc)6-x(OTFA)x] (x = 1-6) formed by a sequential ligand exchange from [Pd3(OAc)6]. Furthermore, we prove that the trinuclear palladium backbone of the precatalyst remains preserved during the first phase of the C-H activation reaction of acetanilides. In other words, the reaction pathway including the trinuclear species should be taken into account in discussion about mechanisms of the reactions catalyzed by palladium acetates.

Aminolysis of ezetimibe.

The aminolysis of ezetimibe (1) and the structurally similar (3R*,4S*)-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-methylazetidin-2-one (4a) giving the corresponding ß-aminoamides 2a-d and 5a-c was studied spectrophotometrically under pseudo-first order conditions in aqueous butylamine, 3-methoxypropylamine, 2-methoxyethylamine and 2-hydroxyethylamine buffer solutions at 39°C. It was found that the reaction mechanism involves uncatalyzed nucleophilic attack of an amine on the azetidinone carbonyl group as the rate-limiting step. On the basis of the Brønsted ß(Nuc) value (0.58 and 0.55 respectively) an early transition state was proposed in which the extent of C-N(amine) bond formation is low and the C-N(lactam) bond remains almost intact. It was also found that the presence of the phenolic group has a crucial role in the aminolysis because the analogous O-methyl derivative 4b does not react with amines at all. This observation would explain the fact that aminolysis of ezetimibe was not observed in human serum albumins where faster glucuronidation which blocks the phenolic hydroxide group occurs.

Kinetics and mechanism of the base-catalyzed rearrangement and hydrolysis of ezetimibe.

The pH-rate profile of the pseudo-first-order rate constants for the rearrangement and hydrolysis of Ezetimibe giving (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide (2) as the main product at pH of less than 12.5 and the mixture of 2 and 5-(4-fluorophenyl)-5-hydroxy-2-[(4-fluorophenylamino)-(4-hydroxyphenyl)methyl]-pentanoic acid (3) at pH of more than 12.5 in aqueous tertiary amine buffers and in sodium hydroxide solutions at ionic strength I = 0.1 mol L(-1) (KCl) and at 39 °C is reported. No buffer catalysis was observed and only specific base catalysis is involved. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple ß-lactams and it contains several breaks. Up to pH 9, the log k(obs) linearly increases with pH, but between pH 9 and 11 a distinct break downwards occurs and the values of log k(obs) slightly decrease with increasing pH of the medium. At pH of approximately 13, another break upwards occurs that corresponds to the formation of compound 3 that is slowly converted to (2R,3R,6S)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxylic acid (4). The kinetics of base-catalyzed hydrolysis of structurally similar azetidinone is also discussed.

Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines.

Variously substituted 2-hydroxy-N-(arylalkyl)benzamides were prepared and screened for antiproliferative and cytotoxic activity in cancer cell lines in vitro. Five compounds, out of 33 showed single-digit micromolar IC50 values against several human cancer cell lines. One of the most potent compounds N-((R)-1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (6k) reduced proliferation and induced apoptosis in the melanoma cell line G361 in a dose-dependent manner, as shown by decrease in 5-bromo-2'-deoxyuridine incorporation and increase in several apoptotic markers, including subdiploid population increase, activation of caspases and site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.

Inverse neighboring group participation: explanation of an unusual S→N alkyl migration of isothiuronium salts containing a lactone group.

A detailed experimental and DFT study of the S to N alkyl migration of substituted S-(1(3H)-isobenzofuranon-3-yl)isothiuronium bromide to N,N'-dimethyl-N-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thiourea provided evidence for the existence of an unusual double displacement mechanism involving two consecutive back-side S(N)2 reactions where a carboxylate anion has a crucial role both as a leaving group as well as an internal nucleophile. The thiazetidine zwitterionic species that is involved in this mechanism as an intermediate was characterized by infrared multiphoton dissociation spectroscopy and was trapped with methyl iodide. It was found that the intermediate has a structure of a free ion pair. The double-displacement mechanism can be considered as a new type of inverse lactone neighboring group participation.

1,2,4-Dithiazole-5-ones and 5-thiones as efficient sulfurizing agents of phosphorus(III) compounds--a kinetic comparative study.

The sulfurization efficiency of 25 3-substituted-1,2,4-dithiazole-5-ones and 5-thiones towards triphenyl phosphite in acetonitrile, DCM, THF and toluene at 25 °C was evaluated. All the 1,2,4-dithiazoles are much better sulfurizing reagents than commercially available agents (PADS, TETD, Beaucage's reagent). The most efficient sulfurizing agents in all solvents are 3-phenoxy (4), 3-phenylthio (5) and 3-ethoxy-1,2,4-dithiazole-5-one (1) whose reactivity is at least two orders of magnitude higher than that of other 1,2,4-dithiazoles. Contrary to a previous report, the sulfurization with 1 does not yield carbonylsulfide and ethyl cyanate as the additional reaction products but unstable ethoxythiocarbonyl isocyanate which has been trapped with 4-methoxyaniline. Similar trapping experiments have proven that the site of attack is at the sulfur adjacent to the C=O group for compounds 4 and 5. The reaction pathway involves rate-limiting initial nucleophilic attack of the phosphorus at sulfur followed by decomposition of the phosphonium intermediate to the corresponding phosphorothioate and isocyanate/isothiocyanate species. The existence of the phosphonium intermediate during sulfurization of triphenyl phosphine with 3-phenyl-1,2,4-dithiazole-5-thione (7a) was proven using kinetic studies. From the Hammett and Brønsted correlations and from other kinetic measurements it was concluded that the transition-state structure is almost apolar for the most reactive 1,2,4-dithiazoles whereas a polar structure resembling a zwitter-ionic intermediate may be more appropriate for the least reactive 1,2,4-dithiazoles. The extent of P­S bond formation and S­S bond cleavage is very similar in all reaction series but it gradually decreases with the reactivity of the 1,2,4-dithiazole derivatives.

Kinetic evidence for the coexistence of zwitterionic (T+/-), neutral (T0) and anionic (T-) intermediates during rearrangement of S-(2-oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)isothiuronium bromide to 5-(2-hydroxyethyl)-2-(4-methoxyphenylimino)-1,3-thiazolidin-4-one.

The kinetics and mechanism of rearrangement of S-(2-oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)isothiuronium bromide (1) into 5-(2-hydroxyethyl)-2-[(4-methoxyphenyl)imino]-1,3-thiazolidin-4-one have been studied under pseudo-first-order reaction conditions in aqueous buffer solutions and in diluted HCl at 25 degrees C. Multiple breaks in the pH profile establish the formation of three different kinetically detectable intermediates T(+/-), T(0), and T(-). Treatment of 1 (pK(a) = 6.7) with base produces reactive isothiourea, which undergoes cyclization to give T(+/-) (rate limiting step at pH < 0.5). Intermediate T(+/-) then undergoes either general acid-catalyzed, concerted (alpha = -0.47) breakdown to 2 (rls at pH 2-3) or a water-mediated proton switch to T(0) which is followed by its general acid-catalyzed breakdown (pH 3-6). The last reaction pathway involves the formation of T(-) either from T(+/-) or from T(0) (pH > 6). The first possibility seems to be more likely because it is in accordance with kinetics observed in basic amine buffers, where the nonlinear increase of the k(obs) with the c(Buffer) changes to a linear increase as a general base-catalyzed pathway is introduced. Coexistence of all three kinetically detectable intermediates is very rare and is possibly due to relatively enhanced stability of these intermediates necessitating participation of an acid for progression to products.

(3RS)-S-[1-(3-Chloro-phen-yl)-2-oxopyr-roli-din-3-yl]thio-uronium bromide.

In the title molecular salt, C(11)H(13)ClN(3)OS(+)·Br(-), the C-N bond lengths in the -S-C(NH(2))(2) fragment indicate partial double-bond character of these bonds. The constituent ions are connected by N-H⋯Br bridges into Z-shaped chains. The supra-molecular architecture of the structure can be described by being composed of these chains inter-locked by additional C-H⋯Br short contacts. An intra-molecular N-H⋯O=C bridge, as well as weak C-H⋯O hydrogen bonds, are also present in the structure.

(3RS)-S-[1-(3-Chloro-phen-yl)-2-oxopyr-rolidin-3-yl]-N,N'-dimethyl-thio-uronium bromide.

The title mol-ecule, C(13)H(17)ClN(3)OS(+)·Br(-), consists of benzene and pyrrolidine rings and an S-C(NHCH(3))(2) group. The central C-N bond lengths in the S-C(NHCH(3))(2) fragment indicate partial double-bond character. Mol-ecules are inter-connected into chains by N-H⋯Br hydrogen bonds and the chains are linked into pairs by weak C-H⋯Br hydrogen bonds.

Mechanism of the sulfurisation of phosphines and phosphites using 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride).

Contrary to a previous report, the sulfurisation of phosphorus(III) derivatives by 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride) does not yield carbon disulfide and cyanamide as the additional reaction products. The reaction of xanthane hydride with triphenyl phosphine or trimethyl phosphite yields triphenyl phosphine sulfide or trimethyl thiophosphate, respectively, and thiocarbamoyl isothiocyanate which has been trapped with nucleophiles. The reaction pathway involves initial nucleophilic attack of the phosphorus at sulfur next to the thiocarbonyl group of xanthane hydride followed by decomposition of the phosphonium intermediate formed to products. The Hammett rho-values for the sulfurisation of substituted triphenyl phosphines and triphenyl phosphites in acetonitrile are approximately -1.0. The entropies of activation are very negative (-114+/-15 J mol-1 K-1) with little dependence on solvent which is consistent with a bimolecular association step leading to the transition state. The negative values of DeltaS(not equal) and rho values indicate that the rate limiting step of the sulfurisation reaction is formation of the phosphonium ion intermediate which has an early transition state with little covalent bond formation. The site of nucleophilic attack has been also confirmed using computational calculations.